A key issue for schizophrenia (SZ) researchers is the identification of heritable phenotypes. Because there are likely multiple SZ vulnerability genes, each of individually weak effect, there are compelling arguments for assessing intermediate phenotypes that can be quantified in individuals without clinical SZ, and might have a simpler genetic basis that is more amenable to linkage and association studies. It has been hypothesized that many schizophrenia vulnerability genes act via influencing cognitive efficiency. In particular, SZ patients and their close relatives tend to show particular deficiencies in working memory, and long-term verbal and spatial explicit memory. Much is known about the neural circuits underlying these distinct types of memory. There are published reports suggesting that several functional polymorphisms in CNS-related genes (that are also known to be SZ vulnerability genes) may influence either memory performance or associated fMRI activation (or both) in controls and in some examples in SZ and their first degree relatives. Thus, the current research will examine the relationship between functional polymorphisms in 4 genes (COMT, BDNF, alpha-7 nicotinic cholinergic, and CB1 cannabinoid receptor) that are believed to influence working and verbal or spatial long-term memory and associated activity in memory-related neural circuits. Subjects will be 100 well-characterized heterogeneous patients with SZ, 100 of their same-sex, close-in-age unaffected siblings and 100 closely matched controls. These data will enable us to clarify the relationship between genotype and brain structure &function in each subject group. We will explore the relationships among specific genes, cognitive performance and circuit-related fMRI activation during each stage of the memory tasks (e.g., encoding vs. retrieval) and psychiatric risk status. Particular emphasis will be placed on determining how functional polymorphisms influence distinct aspects of memory function for both verbal and nonverbal material, in an attempt to elucidate the functional impact of putative vulnerability genes on cognitive efficiency and to identify reliable SZ endophenotypes. The planned project is highly collaborative between experts in structural and functional neuroimaging, cognitive testing, clinical assessment and genotyping. It will be conducted in a recently established neuroimaging research center with direct access to large numbers of SZ patients and their siblings.